DESCRIPTION: This research project will establish a strategy to evaluate potential health implications resulting from exposure to complex mixtures of organophosphate (OP) insecticides. OP insecticides are widely utilized in a variety of applications and potential exists for significant occupational exposure. The health implications of mixed chemical exposures are currently poorly understood, since the toxicological characterization of such complex mixtures is not practical due to the numerous potential combinations. To address this chemical mixture issue, an integrated approach is proposed involving the application of physiologically-based pharmacokinetic/ pharmacodynamic (PBPK/PD) modeling in conjunction with focused in vivo/ in vitro studies. The goal of this project is to provide a quantitative understanding of complex chemical interactions within biological systems, estimate tissue dosimetry, and quantitate pharmacodynamic response (i.e. esterase inhibition). This approach represents a reasonable application of limited resources (i.e. time and funding) to generate data which can be used to evaluate human health risk from occupational exposure to important agricultural chemicals. Specific research aims include: to develop a PBPK/PD model for diazinon (DZN) in the rat; to conduct focused in vitro experiments in rats to quantify critical metabolic interactions for mixtures of chlorpyrifos (CPF) and DZN that can readily be incorporated into a binary mixture PBPK/PD model; to conduct in vivo evaluations of the PBPK/PD model interactions for mixtures of CPF and DZN in the rat and to conduct focused in vitro experiments with human tissues to quantify critical metabolic interactions and to develop a human DZN and binary OP mixture PBPK/PD model.